CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases.

Department of Biochemistry, University of Delhi, South Campus, New Delhi, India.

Abstract

The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.

Phylogenetic analysis of CUL4A protein in eukaryotic species. The table compares sequence identity of Cul4A of various eukaryotes with human CUL4A. Below the table, the phylogenetic tree represents the evolutionary relationship between these organisms. Relationship was inferred using PHYLIP (Kitsch) program and the tree was visualized using PhyloDraw. Depicted here is a schematic representation.